Free-energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are ...still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free-energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace, and OpenMM and uses the AMBER 14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset, the average correlation coefficient
was 0.70 ± 0.05 and average Kendall's τ was 0.53 ± 0.05, which are broadly comparable to or better than previously reported results using other methods.
A general purpose force field such as MMFF94/MMFF94s, which can properly deal with a wide range of diverse structures, is very valuable in the context of a cheminformatics toolkit. Herein we present ...an open-source implementation of this force field within the RDKit. The new MMFF functionality can be accessed through a C++/C#/Python/Java application programming interface (API) developed along the lines of the one already available for UFF in the RDKit. Our implementation was fully validated against the official validation suite provided by the MMFF authors. All energies and gradients were correctly computed; moreover, atom type and force constants were correctly assigned for 3D molecules built from SMILES strings. To provide full flexibility, the available API provides direct access to include/exclude individual terms from the MMFF energy expression and to carry out constrained geometry optimizations. The availability of a MMFF-capable molecular mechanics engine coupled with the rest of the RDKit functionality and covered by the BSD license is appealing to researchers operating in both academia and industry.
A methodology that combines alchemical free energy calculations (FEP) with machine learning (ML) has been developed to compute accurate absolute hydration free energies. The hybrid FEP/ML methodology ...was trained on a subset of the FreeSolv database and retrospectively shown to outperform most submissions from the SAMPL4 competition. Compared to pure machine-learning approaches, FEP/ML yields more precise estimates of free energies of hydration and requires a fraction of the training set size to outperform standalone FEP calculations. The ML-derived correction terms are further shown to be transferable to a range of related FEP simulation protocols. The approach may be used to inexpensively improve the accuracy of FEP calculations and to flag molecules which will benefit the most from bespoke force field parametrization efforts.
The electric vehicle (EV) market is growing rapidly due to the necessity of shifting from fossil fuel-based mobility to a more sustainable one. Smart charging paradigms (such as vehicle-to-grid ...(V2G), vehicle-to-building (V2B), and vehicle-to-home (V2H)) are currently under development, and the existing implementations already enable a bidirectional energy flow between the vehicles and the other systems (grid, buildings, or home appliances, respectively). With regard to grid connection, the increasingly higher penetration of electric vehicles must be carefully analyzed in terms of negative impacts on the power quality; and hence, the effects of electric vehicle charging stations (EVCSs) must be considered. In this work, the interactions of multiple electric vehicle charging stations have been studied through laboratory experiments. Two identical bidirectional DC chargers, with a rated power of 11 kW each, have been supplied by the same voltage source, and the summation phenomenon of the current harmonics of the two chargers (which leads to an amplification of their values) has been analyzed. The experiment consisted of 100 trials, which considered four different combinations of power set-points in order to identify the distribution of values and to find suitable indicators for understanding the trend of the harmonic interaction. By studying the statistical distribution of the Harmonic Summation Index, defined in the paper, the impact of the harmonic distortion caused by the simultaneous charging of multiple electric vehicles has been explored. Based on this study, it can be concluded that the harmonic contributions of the electric vehicle charging stations tend to add up with increasing degrees of similarity of the power set-points, while they tend to cancel out the more the power set-points differ among the chargers.
Cyclooxygenase (COX) carries out stereospecific oxygen addition to arachidonic acid to generate prostaglandins, plus smaller amounts of 11- and 15-hydroxyeicosatetraenoic acids. For COX-2, the ...stereochemistry and relative abundance of generated products is influenced by Ser530 acetylation following aspirin treatment. The molecular bases of the high degree of stereospecificity which characterizes COX-2-catalyzed oxygenations are not yet completely understood, nor are the reasons behind the aspirin-induced shift in lipid mediator production. A mechanistic hypothesis is proposed which identifies steric shielding as the main determinant of oxygenation stereospecificity. This hypothesis is supported by a computational model which accurately reproduces experimental oxygenation patterns on both native and aspirin-inhibited COX-2.
Open3DQSAR is a freely available open-source program aimed at chemometric analysis of molecular interaction fields. MIFs can be imported from different sources (GRID, CoMFA/CoMSIA, quantum-mechanical ...electrostatic potential or electron density grids) or generated by Open3DQSAR itself. Much focus has been put on automation through the implementation of a scriptable interface, as well as on high computational performance achieved by algorithm parallelization. Flexibility and interoperability with existing molecular modeling software make Open3DQSAR a powerful tool in pharmacophore assessment and ligand-based drug design.
Figure
Open3DQSAR’s logo displaying PLS coefficient isocontours
Purpose This retrospective study evaluated the long-term results and complications of open reduction and internal fixation of displaced and dislocated fractures of the condylar process. Patients and ...Methods Two hundred four patients were treated via various surgical approaches between 1991 and 2005. Fifty patients with a total of 57 treated condylar fractures who underwent complete clinical and radiological documentation were included in this study. Follow-up clinical and radiological evaluations were carried out after an average period of 88 months. Results We found that 12% of our patients reported temporary weakness of the facial nerve and 4% had mild permanent facial nerve palsy. Clinical and radiological assessment showed satisfactory recovery of facial symmetry. Excellent recovery of function was observed, and very few patients complained of temporomandibular joint-related symptoms. Severe condylar remodeling was observed in 8% of the patients, 47% showed slight or moderate remodeling, and 45% showed no remodeling. A statistically significant association was observed between the presence of condylar remodeling and poor mouth opening at the follow-up examination. Conclusions Surgical treatment of condylar fractures, in association with postoperative functional therapy, promotes the recovery of function, occlusion, and facial symmetry with few complications. However, some difficulties remain related to the surgeon, the patient, and the objective complexity of this pathology.
A method for predicting the binding mode of a series of ligands is proposed. The procedure relies on three-dimensional quantitative structure–activity relationships (3D-QSAR) and does not require ...structural knowledge of the binding site. Candidate alignments are automatically built and ranked according to a consensus scoring function. 3D-QSAR analysis based on the selected binding mode enables affinity prediction of new drug candidates having less than 10 rotatable bonds.
An open-source, cross-platform software aimed at conformer generation and unsupervised rigid-body molecular alignment is presented. Different algorithms have been implemented to perform single and ...multi-conformation superimpositions on one or more templates. Alignments can be accomplished by matching pharmacophores, heavy atoms or a combination of the two. All methods have been successfully validated on eight comprehensive datasets previously gathered by Sutherland and co-workers. High computational performance has been attained through efficient parallelization of the code. The unsupervised nature of the alignment algorithms, together with its scriptable interface, make Open3DALIGN an ideal component of high-throughput, automated cheminformatics workflows.
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